P.I. Responsible: Carlos Simón, MD, PhD
Lab. Technician: Alicia Quiñonero and Sebastian Martinez
Epigenetic study of endometrial receptivity and decidualization:
Many events during the menstrual cycle are associated with epigenetic changes. The endometrium receptivity state acquisition and posterior decidualization is associated with transcriptional and post-transcriptional changes that are controlled by the different epigenetic mechanisms such us DNA methylation, histone modifications and non coding RNAs. Image modified from Munro et al, 2010. Molecular Human Reproduction.
Embryo implantation consists on the adhesion of the competent embryo to the endometrial luminal epithelium followed by the invasion of the stromal compartment underneath. The regulation of this process is still unknown, but two thirds of the implantation failures are due to endometrial receptivity defects . Implantation failures could have consequences apart from infertility, such us intrauterine growth restriction, preeclampsia, premature birth or fetal loss. A prerequisite for embryo adhesion is the transdetermination of the endometrium from a “pre-receptive” state to a “receptive” one . The luminal epithelium acquires its “receptive” state by the action of the female steroid hormones, progesterone and estradiol. The stromal cells that surround the embryonic implantation site suffer a differentiation process known as decidualization, essential for the pregnancy success. This differentiation event is linked to morphological, biochemical and genetic changes triggered by the receptors of estradiol and progesterone. The function of the maternal decidua is to control the trophoblast invasion, to promote the development of blood vessels and the formation of the placenta . Defects during this process are associated to pregnancy complications as the ones described above. Both events, the transdetermination of the endometrium from the “pre-receptive” to the” receptive” state, and the decidualization, have been studied intensively at the transcriptional and proteomic level, helping us indentify those genes differentially expressed. Despite all this information we still lack the molecular and functional mechanisms that control these processes and how the deregulation is associated to implantation and decidualization defects.
The field of epigenetics studies the alterations in the gene function that are mitotically or meiotically heritable and that do not entail changes in the DNA sequence . Epigenetic modifications change the chromatin structure affecting gene expression control during the development of an organism and their misregulation is associated to some diseases such as cancer . These epigenetic modifications can be mediated by DNA methylation, histone modifications or non coding RNA. DNA methylation is a key gene regulatory process that mediates gene imprinting, X chromosome inactivation or aging. In mammals gene methylation occurs mainly in the CpGs close to gene promoters (CpGs islands) and is associated to gene repression. Around 3-6% of the cytosines are methylated and this methylation is responsible for the tissue specific gene expression . Alterations of the gene methylation state are associated to some diseases such as cancer, due to the deregulation of some oncogenes and some tumor supresor genes .
Other epigenetic modifications are the non coding RNA, especially microRNAs (miRNAs) that are post-transcriptionally regulators of gene function . miRNAs are small sequences, 22 nucleotides of non coding RNA that binds to the 3´UTRs of target genes by sequences complementarity. One miRNA can regulate more than 100 target genes and it is estimated that more than 30% of the genome is regulated by these small RNAs. miRNAs are differentially expressed depending on the tissue and regulate multitude of biological processes as differentiation, proliferation or apoptosis . miRNAs deregulation is associated to multiple cardiovascular, neurodegenerative and cancer diseases and some reproductive ones, such as endometriosis or endometrial cancer  .
It is logic to think that all the endometrial functional changes that occur during the menstrual cycle (endometrial receptivity, decidualization, etc.) are epigenetically regulated by DNA methylation, histone modification and miRNAs.
In our laboratory we are currently developing two main research lines:
1.- Epigenetic control of endometrial receptivity. We are analyzing the changes at the DNA methylation and miRNA level that controls the acquisition of the receptive state of the endometrium.
2.- Epigenetic control of the decidualization process. As in the first point we are studying the DNA methylation and miRNA changes that control this process. For this purpose we have developed an in vitro decidualization assay of endometrial cells by the administration of estradiol and progesterone that allow us to study in detail the epigenetic control of this process.
- Simon, C., et al., Cytokines and embryo implantation. J Reprod Immunol, 1998. 39(1-2): p. 117-31.
- Dey, S.K., et al., Molecular cues to implantation. Endocr Rev, 2004. 25(3): p. 341-73.
- Ramathal, C.Y., et al., Endometrial decidualization: of mice and men. Semin Reprod Med, 2010. 28(1): p. 17-26.
- Berger, S.L., et al., An operational definition of epigenetics. Genes Dev, 2009. 23(7): p. 781-3.
- Feinberg, A.P., Phenotypic plasticity and the epigenetics of human disease. Nature, 2007. 447(7143): p. 433-40.
- Esteller, M., Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet, 2007. 8(4): p. 286-98.
- Berdasco, M. and M. Esteller, Aberrant epigenetic landscape in cancer: how cellular identity goes awry. Dev Cell, 2010. 19(5): p. 698-711.
- Ambros, V., The functions of animal microRNAs. Nature, 2004. 431(7006): p. 350-5.
- Singh, S.K., et al., MicroRNAs--micro in size but macro in function. FEBS J, 2008. 275(20): p. 4929-44.
- Teague, E.M., C.G. Print, and M.L. Hull, The role of microRNAs in endometriosis and associated reproductive conditions. Hum Reprod Update, 2010. 16(2): p. 142-65.